HIV Infection Related Tuberculosis: Clinical Manifestations and Treatment

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1 SUPPLEMENT ARTICLE HIV Infection Related Tuberculosis: Clinical Manifestations and Treatment Timothy R. Sterling, 1 Paul A. Pham, 2 and Richard E. Chaisson 2 1 Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, and 2 Division of Infectious Diseases and Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland Several aspects of human immunodeficiency virus (HIV) infection related tuberculosis (TB) and its treatment differ from those of TB in HIV-uninfected persons. The risk of TB and the clinical and radiographic manifestations of disease are primary examples. Antiretroviral therapy has a profound effect on lowering the risk of TB in HIV-infected persons, but it can also be associated with immune reconstitution inflammatory disease and unmasking of previously subclinical disease. There are also differences in treatment of HIV infection related TB because of overlapping drug toxicities and drug-drug interactions between antiretroviral therapy and anti-tb therapy. Tuberculosis (TB) is one of the most common complications of human immunodeficiency virus (HIV) infection and a leading cause of death. Although highly publicized outbreaks of drug-resistant TB have occurred in recent years, most HIV-related TB is caused by drug-susceptible strains. There are a number of special challenges in the management of TB in HIV-infected persons, compared with HIV-uninfected persons, and these challenges are the primary emphasis of this review. CLINICAL MANIFESTATIONS OF TB Pulmonary disease. Although HIV-infected persons with TB may have the classic symptoms of TB (eg, productive cough, chest pain, shortness of breath, hemoptysis, fever, night sweats, and/or weight loss), many such patients have few symptoms or have symptoms that are even less specific than those mentioned. It has been noted recently that a small proportion of HIVinfected patients with TB are minimally symptomatic or asymptomatic, particularly in developing countries Reprints or correspondence: Dr Timothy R. Sterling, A2209 Medical Center North, st Ave South, Nashville, TN (timothy.sterling@vanderbilt.edu). Clinical Infectious Diseases 2010; 50(S3):S223 S by the Infectious Diseases Society of America. All rights reserved /2010/5010S3-0021$15.00 DOI: / with a high burden of both HIV infection and TB [1, 2]. In addition, many HIV-infected patients with TB particularly patients with advanced HIV disease and low CD4 + T lymphocyte counts have atypical chest radiograph findings [3, 4]. For example, HIV-infected patients with TB are less likely to have cavitary pulmonary disease than are HIV-uninfected patients with TB, and up to 22% of HIV-infected persons with pulmonary TB have normal chest radiograph findings [5 7]. Smear-negative pulmonary disease. Consistent with the lower prevalence of cavitary disease, HIV-infected patients with TB have acid-fast smear-negative disease more frequently than do HIV-uninfected persons [8]. Because sputum smear is the principal means of detecting TB in much of the world, smear-negative patients often do not receive a diagnosis and are often not treated promptly, if at all. The mortality rate is higher among such patients than among HIV-infected patients with smear-positive TB (because of delays in TB diagnosis in the former) and higher than among HIV-uninfected persons with smear-negative disease (because of HIV infection) [9]. Subclinical disease. Because of the aforementioned findings, it should not be surprising that HIV-infected patients with TB may frequently have so-called subclinical TB. Such disease is not recognized as TB, resulting in delays in diagnosis and treatment. Often the HIV Infection Related TB CID 2010:50 (Suppl 3) S223

2 manifestations of TB do not become apparent until the patient has initiated antiretroviral therapy (see Effect of Highly Active Antiretroviral Therapy [HAART] on TB Risk and Clinical Manifestations ). The natural history of subclinical TB in HIVinfected persons is not well understood. Unlike individuals without HIV infection, in whom TB may be a chronic, lowgrade condition, persons with HIV infection almost always experience progression of TB disease, ultimately leading to death in the absence of effective treatment. Thus, subclinical TB may represent the early stages of the disease that will inevitably progress to overt illness. Extrapulmonary disease. HIV-infected persons are also more likely than HIV-uninfected persons to have extrapulmonary TB, which may or may not occur with concomitant pulmonary disease. Forty percent to 80% of HIV-infected persons with TB have extrapulmonary disease, compared with 10% 20% of HIV-uninfected persons [10]. The risk of extrapulmonary TB increases with lower CD4 + T lymphocyte count [11]. The most common forms of extrapulmonary disease are lymphatic and pleural, but almost any site can be involved, including the bone and/or joint (particularly the thoracic spine), soft tissue (eg, psoas muscle, which may be associated with spinal disease), central nervous system, and pericardium. TREATMENT OF HIV INFECTION RELATED TB In principle, the treatment of TB in individuals with HIV infection should be the same as that for patients with TB who do not have HIV disease. Standard first-line therapy for TB with a 4-drug intensive treatment phase of 2 months, followed by 4 months of treatment with a 2-drug regimen, is highly effective in patients with HIV infection related TB (Table 1). Unlike treatment of HIV-uninfected patients, however, treatment of HIV-infected patients with TB presents a myriad of clinical challenges regarding the duration of treatment, frequency of administration, management of drug interactions, and complications of therapy, such as drug toxicity and immune reconstitution disease. Because such patients are being treated for 2 diseases, the goals of therapy for both must be balanced so that optimal outcomes in terms of treatment response and prevention of drug resistance are achieved for both conditions. Early reports of treatment outcomes in patients with HIV infection related TB revealed that initial outcomes were generally very good, but long-term outcomes were poor because of HIV infection related mortality [10]. In recent years, because of more-effective treatment of HIV infection, long-term outcomes of TB therapy have improved, and additional problems, such as recurrent TB, drug-drug interactions, and overlapping drug toxicities, have emerged. Duration of treatment. Because initial responses to therapy are mostly excellent in both HIV-infected and HIV-uninfected patients, the optimal duration of TB treatment is determined by risk of relapse. Currently, treatment guidelines recommend that the duration of TB therapy should be the same for both HIV-infected and HIV-uninfected persons [12 14]. For pulmonary infection with drug-susceptible Mycobacterium tuberculosis, a 6-month course of rifamycin-based therapy is the standard of care [12], because of comparable rates of TB relapse among persons receiving 6-month regimens of rifamycin-based therapy (eg, rifampin or rifabutin) [15 18]. However, most of the studies that have shown equal efficacy were relatively small and not randomized. Only 2 randomized trials have been reported on relapse rate among HIV-infected persons with TB, compared with that among HIV-uninfected patients with TB, who receive 6 months of rifamycin-based therapy [19, 20]. These studies, both performed in settings with very high community rates of TB, showed that a longer duration of therapy was associated with a lower short-term recurrence rate. Perriens et al [19], working in former Zaire, found that 12 months of standard rifampin-based therapy resulted in a significantly lower recurrence rate at 18 months, compared with a 6-month regimen. Fitzgerald et al [20] studied HIV-infected and HIVuninfected patients with TB in Haiti and found that recurrences were significantly reduced only among HIV-infected patients when isoniazid was continued for 1 year after a 6-month standard regimen for TB. In neither study were the investigators able to distinguish relapse from reinfection, and patients did not have access to antiretroviral therapy. Nonetheless, these trials suggest that, in high-burden areas, the likelihood of recurrent TB is reduced by either longer treatment of the initial episode or secondary prophylactic (suppressive) therapy with isoniazid. In addition, several observational studies have suggested that the relapse rate after such therapy may be higher among HIV-infected persons than among HIV-uninfected persons, with rates of 2% among HIV-uninfected persons and as high as 9% among HIV-infected persons [21 23]. In an observational cohort study involving South African gold miners, Churchyard et al [24] found that secondary isoniazid preventive therapy reduced the risk of recurrent TB substantially. The primary risk factor for TB recurrence among HIV-infected patients with TB appears to be low CD4 + T lymphocyte count, with the risk highest among persons with a CD4 + T lymphocyte count!100 cells/mm 3 [22, 23]. Low CD4 + T lymphocyte count appears to be a stronger risk factor than the factors that are associated with relapse in HIV-seronegative persons: cavitary pulmonary disease, positive sputum culture result after 2 months of treatment, bilateral pulmonary disease, low body weight, and white race [22, 25]. However, large-scale comparative studies of risk factors for relapse in HIV-infected persons with TB, compared with that in HIV-uninfected patients with TB, are needed. A recent study from Botswana found that low pyrazinamide concentrations were associated with poor S224 CID 2010:50 (Suppl 3) Sterling et al

3 Table 1. Recommendations for the Treatment of HIV Infection Related Tuberculosis Treatment Regimen Comments Induction phase (8 weeks) INH, RIF, PZA, EMB daily or 3 times weekly Strongly consider initiation of antiretroviral therapy, especially for advanced HIV disease; directly observed therapy recommended; in high-burden settings, also give TMP-SMX daily Induction phase (8 weeks) with antiretroviral agents INH, RIF, PZA, EMB daily or 3 times weekly with efavirenz-based regimen; nevirapine may also be given with RIF with caution; substitute RBT for RIF, 3 times weekly with ritonavir-boosted PI regimen; substitute RBT for RIF, daily with nevirapinebased regimen No dose adjustments needed; directly observed therapy recommended Continuation phase (18 weeks) INH, RIF daily or 3 times weekly Directly observed therapy recommended Continuation phase with antiretroviral agents (18 weeks) INH, RIF daily or 3 times weekly with efavirenz- or nevirapine- based regimen; substitute RBT for RIF, 3 times weekly with daily ritonavir-boosted PI regimen; substitute RBT for RIF, daily with nevirapinebased regimen Directly observed therapy recommended NOTE. EMB, ethambutol; INH, isoniazid; PI, protease inhibitor; PZA, pyrazinamide; RBT, rifabutin; RIF, rifampin; TMP-SMX, trimethoprim-sulfamethoxazole. treatment outcome (defined as treatment failure or death), after adjusting for HIV infection and CD4 + T lymphocyte count [26]. Intermittent treatment. Intermittent TB therapy, given under direct observation, is a key component of TB treatment regimens in the United States and elsewhere. Although TB relapse rates were low in the randomized, controlled clinical trials that formed the basis of such treatment recommendations [27], intermittent therapy has been associated with higher relapse rates than daily therapy in some observational studies [28, 29]. Of particular concern in HIV-infected persons is relapse of TB with rifamycin resistance that was not present on the original M. tuberculosis isolate (ie, acquired rifamycin resistance) [30, 31]. Risk factors for acquired rifamycin resistance include advanced HIV disease (eg, CD4 + T lymphocyte count!100 cells/ mm 3 ), highly intermittent anti-tb therapy (eg, once or twice weekly), and low drug levels of both rifamycins and isoniazid [32 34]. Table 1 lists current recommended regimens for the treatment of HIV infection related TB. Treatment of HIV infection related TB in pregnant women. TB should be treated in all pregnant women, including those with HIV infection. Treatment should include isoniazid, rifampin, and ethambutol. Aminglycosides, such as streptomycin, should not be used, because of their potential for causing congenital deafness. Recommendations regarding the use of pyrazinamide in pregnancy vary: it is not recommended in the United States because of limited safety data, but its use in pregnancy is recommended by the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease [13, 35, 36]. The use of rifampin during TB therapy in pregnant women is essential, but management of drug-drug interactions is particularly challenging, as discussed in Drug Interactions between Rifamycins and Antiretroviral Therapy. Treatment with trimethoprim-sulfamethoxazole. In 1999, Wiktor et al [37] reported that trimethoprim-sulfamethoxazole, given 1 month after initiation of anti-tb therapy, reduced mortality by 46% among HIV-1 and HIV-2 coinfected patients with TB in Côte D Ivoire. Of note, the median CD4 + T lymphocyte count in the study patients was 317 cells/mm 3, and antiretroviral therapy was not available. Use of trimethoprimsulfamethoxazole appeared to reduce the risk of death by preventing gastrointestinal and respiratory infections in this resource-poor setting. As a result, the WHO and the United Nations Joint Programme on HIV/AIDS (UNAIDS) recommend that all patients with HIV infection related TB be treated with trimethoprim-sulfamethoxazole during and after treatment for TB. In developed countries and in countries with good access to antiretroviral therapy, the level of relevance of this recommendation is not apparent. In the United States, for example, the use of trimethoprim-sulfamethoxazole is restricted to patients with CD4 + T lymphocyte counts!200 cells/mm 3 for pneumocystis prophylaxis. But in settings where enteric infections, malaria, and bacterial respiratory infections are more common, adherence to the recommendation of the WHO and UNAIDS is warranted for patients with HIV infection related TB. Posttreatment isoniazid. HIV infection is associated with high rates of recurrent TB, particularly in developing countries [38]. However, in such settings, recurrent disease is more likely to be attributable to exogenous reinfection than to relapse [38, 39]. A course of isoniazid after completion of standard anti- TB treatment has been associated with lower rates of TB re- HIV Infection Related TB CID 2010:50 (Suppl 3) S225

4 currence, particularly among HIV-infected persons [20, 24]. Although this strategy has been proven to be effective in settings with a high incidence of TB and HIV infection, it is often not provided because of logistical constraints. EFFECT OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) ON TB RISK AND CLINICAL MANIFESTATIONS The risk of TB among HIV-infected persons not receiving antiretroviral therapy is high, with rates ranging from 720 cases per 100,000 population in the United States [40] to 8400 cases per 100,000 population in Brazil [41] and 9700 cases per 100,000 population in South Africa [42]. On a population level, there has been a remarkably consistent 80% decrease in TB risk among persons who receive HAART [40 42]. However, even after several years of HAART, the risk of TB remains higher than that in HIV-uninfected persons, suggesting that immune restoration is not complete [43, 44]. This finding is also an important reminder to clinicians that HIV-infected persons receiving stable HAART remain at increased risk of TB, compared with HIV-uninfected persons. Although immune reconstitution because of HAART has long-term benefits with regard to risk of TB, it can also unmask TB not clinically recognized before HAART initiation (ie, subclinical disease). Such HAART-associated TB can sometimes be associated with the immune reconstitution inflammatory syndrome [45, 46]. Consistent with this phenomenon, risk of TB is particularly high during the first 3 months of HAART [43, 44, 47]. It is unclear whether HAART is associated with an initial increase in risk of TB, compared with persons not receiving antiretroviral therapy. THE OPTIMAL TIMING OF HAART INITIATION IN PERSONS WITH HIV INFECTION RELATED TB Among HIV-infected persons who receive a diagnosis of TB and do not receive HAART, the mortality rate is high (as high as 91% among persons with AIDS) [10, 48, 49]. Initiation of HAART is associated with improved survival among all HIVinfected persons, including those with TB [50 54]. It is therefore recommended that HIV-infected patients with TB receive treatment for both diseases, regardless of their CD4 + T lymphocyte count. However, the optimal timing of HAART initiation in relation to the time of anti-tb therapy initiation is unclear. In contrast to the survival benefit provided by HAART, the disadvantages of concomitant treatment of both diseases include a high pill burden, multiple and overlapping drug toxicities, and the possibility of paradoxical worsening of TB in the context of immune reconstitution. In addition, there are drug-drug interactions, particularly between rifamycins and several potent antiretroviral therapy agents. Both the risks and benefits of concomitant therapy are greatest among persons with low CD4 + T lymphocyte counts. High pill burden for treatment of TB and HIV infection. Standard daily rifamycin-based anti-tb therapy includes 4 medications plus vitamin B6, with a daily pill burden of 110 pills. Antiretroviral therapy can vary from a single pill (eg, efavirenz plus emtricitabine plus tenofovir) to several pills (eg, a ritonavir-boosted protease inhibitor plus 2 nucleoside reversetranscriptase inhibitors). Patients often receive additional medications, including prophylaxis for opportunistic infections [55]. Overlapping toxicity of treatment of TB and HIV infection. Hepatotoxicity is a common adverse effect of isoniazid, the rifamycins, and pyrazinamide. It also occurs frequently with HIV-1 protease inhibitors and nonnucleoside reverse-transcriptase inhibitors. Underlying HIV infection may also contribute to the risk, and concomitant hepatitis C virus infection further increases the risk [56]. Other adverse effects, such as gastrointestinal upset and rash, are common with both types of medications. Although stavudine and didanosine are less frequently used for the treatment of HIV infection, they can cause peripheral neuropathy, as can isoniazid. Immune reconstitution inflammatory syndrome. Immune reconstitution inflammatory syndrome can occur in the context of improved CD4 + T lymphocyte count and HIV-1 RNA level in persons receiving HAART. Although the clinical manifestations of several opportunistic infections can be affected, TB is among the most common [57]. Clinical manifestations include new or enlarging lymph nodes, worsening radiological features, new or worsening central nervous system TB, and new or worsening serositis. Common clinical manifestations include fever, cough, dyspnea, or abdominal pain (the latter due to organomegaly or serositis) [58]. Although the debate continues about optimal timing of HAART initiation in individuals with active TB, there are several ongoing clinical trials assessing this issue [59]. The Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT) trial reported preliminary findings that survival was improved among persons initiating HAART during anti-tb therapy, compared with waiting until after completion of anti-tb therapy [60]. A second phase of the study is comparing HAART initiation within 2 months with HAART initiation 2 6 months after anti-tb therapy initiation. Several other controlled clinical trials addressing this issue are also under way. A randomized trial of immediate versus deferred HAART in patients with HIV-related TB meningitis in Vietnam recently reported an increased rate of adverse reactions among those treated early, with no difference in mortality or progression of HIV disease [61]. Use of HAART in patients with active infection of the central nervous system, such as TB or cryptococcal meningitis, may lead to immune reconstitution inflammatory events with S226 CID 2010:50 (Suppl 3) Sterling et al

5 Table 2. Management of Interactions among Drugs Used to Treat Tuberculosis (TB) and HIV Infection HIV infection treatment TB treatment Interaction Recommendation PIs, unboosted (no ritonavir) Atazanavir, indinavir, nelfinavir, and saquinavir Rifampin Rifampin reduces C max, AUC, and trough by 180% Atazanavir, indinavir, and nelfinavir Rifabutin Increased concentrations of rifabutin with variable effects on PI exposure PIs, boosted (with ritonavir) Lopinavir, fosamprenavir, atazanavir, indinavir, darunavir, and tipranavir Rifampin Rifabutin Rifampin reduces C max, AUC, and trough significantly; double dosing of PI is toxic and may not overcome interaction Modest decreases in PI exposure; ritonavir increases rifabutin exposure, potentially resulting in toxicity Nonnucleoside reverse-transcriptase inhibitors Efavirenz Rifampin Rifampin reduces efavirenz exposure by 20% Rifabutin Efavirenz increases rifabutin clearance by 30% 40% Nevirapine Rifampin Rifampin reduces nevirapine AUC by 37% 58% and C min by 37% 68% Do not coadminister Rifabutin and unboosted PIs may be coadministered (with dose adjustment), but alternative regimens are preferred because of limited safety and efficacy data Do not use Usual PI administered with ritonavir; rifabutin dosage of 150 mg every other day Administer both drugs at usual doses; some recommend increasing efavirenz dose to 800 mg Rifabutin dosage should be increased to mg daily or 600 mg 3 times weekly Avoid combination if possible because of higher rate of virological failure; use of full-dose nevirapine (200 mg twice daily) with rifampin may be effective Rifabutin Minimal interactions May be coadministered safely at usual doses Etravirine Rifampin Significant interaction of rifampin on Do not coadminister etravirine exposure Rifabutin Modest bidirectional interaction with reductions in exposure to both agents May be coadministered with rifabutin dosage of 300 mg daily; do not coadminister with DRV/r or SQV/r in regimen because of interaction between etravirine and DRV/r or SQV/r Integrase inhibitors Raltegravir Rifampin Rifampin reduces C max, AUC, and trough levels by 60% 70%; doubling raltegravir dosage to 800 twice daily improves C max and AUC but does not affect reduction in trough concentration Rifabutin Rifabutin reduces raltegravir trough by 20%, but raltegravir AUC is not affected Coreceptor inhibitors Maraviroc Rifampin Rifampin reduces maraviroc exposure by 160% Rifabutin Modest impact of rifabutin on maraviroc exposure likely Fusion inhibitors Do not coadminister; consider rifabutin with raltegravir coadministration Administer rifabutin (300 mg daily) with raltegravir (400 mg twice daily) Do not coadminister, or increase maraviroc dosage to 600 mg twice daily Administer maraviroc (300 mg twice daily) and rifabutin (300 mg daily) Enfuvritide Rifampin and rifabutin No interactions No dose adjustments necessary Nucleoside analogues Zidovudine Rifampin Rifampin reduces zidovudine AUC by 47%, but effect on intracellular concentrations unknown Clinical significance unknown NOTE. Additional information is available at [63]. AUC, area under the curve; C max, maximum plasma concentration of drug; C min, minimum concentration of drug; DRV/r, darunavir booseted with ritonavir; PI, protease inhibitor; SQV/r, saquinavir boosted with ritonavir. particularly adverse outcomes, unlike treatment in patients with opportunistic infection of other organ systems. A decision analysis addressing the timing of initiation of HAART for persons with active TB and CD + T lymphocyte counts!200 cells/mm 3 that used data from developed countries (because data from developing countries were not available) found that HAART initiation during the first 2 months of anti-tb therapy was associated with improved outcomes, compared with HAART initiation during months 2 6 of anti-tb therapy or after completion of anti-tb therapy [62]. HIV Infection Related TB CID 2010:50 (Suppl 3) S227

6 DRUG INTERACTIONS BETWEEN RIFAMYCINS AND ANTIRETROVIRAL THERAPY The primary drug-drug interactions of concern are those between rifamycins and HIV-1 protease inhibitors, nonnucleoside reverse transcriptase inhibitors, integrase inhibitors, and CCR5 inhibitors. Table 2 summarizes the major interactions between the rifamycins used to treat TB and antiretroviral agents. HIV-1 protease inhibitors. Rifampin significantly decreases HIV-1 protease inhibitor levels and, therefore, should generally not be given in combination with this drug class. Drug interaction studies have shown that rifampin could possibly be given with ritonavir (standard dose, not pharmacological boosting dose) or high-dose lopinavir plus ritonavir; however, the former is generally no longer used for treatment of HIV infection, and the latter combination has been associated with hepatitis [63]. Rifabutin can be given with HIV-1 protease inhibitors, but the rifabutin dose must be decreased to avoid toxicity. When given in combination with any dose of ritonavir (including ritonavir for pharmacologic boosting), the dosage of rifabutin should be decreased to 150 mg every other day or 3 times per week. Rifabutin has recently been added to the WHO s Essential Drug List, but it is not widely available in developing countries. Nonnucleoside reverse transcriptase inhibitors. Rifampin can be given with efavirenz or nevirapine, but there is increasing evidence that virological outcomes are better with efavirenz than with nevirapine [64, 65]. Rifampin causes a 22% decrease in the area under the curve of efavirenz. This generally does not affect virologic outcomes, but some experts recommend increasing the efavirenz dose to 800 mg, particularly in persons weighing 160 kg [63]. Integrase inhibitors. Rifampin decreases raltegravir concentrations by 40% 61%; thus, this combination should generally not be given [63]. There are no clinically significant drug interactions between rifabutin and raltegravir [66]. CCR5 inhibitors. Rifampin decreases maraviroc concentrations by 78%; although the maraviroc dose could be increased to 600 mg twice daily, there are no clinical data on this increased dose and combination. There are no data on the interaction between rifabutin and maraviroc [63]. CONCLUSIONS The frequency of TB among patients with HIV infection proves that TB diagnosis, treatment, and prevention are essential for all clinicians caring for persons infected with HIV. Although the treatment of HIV-related TB with standard anti-tb regimens is usually highly effective, managing the important drug interactions, toxicities, and immune reconstitution inflammatory syndrome makes care of coinfected patients particularly challenging. 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